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27 Respiratory system

Overview

Basic aspects of respiratory physiology (regulation of airway smooth muscle, pulmonary vasculature and glands) are considered as a basis for a discussion of pulmonary disease and its treatment. We devote most of the chapter to asthma, dealing first with pathogenesis and then the main drugs used in its treatment and prevention—inhaled bronchodilators and anti-inflammatory agents. We also discuss chronic obstructive pulmonary disease (COPD). There are short sections on allergic emergencies, surfactants and the treatment of cough. Other important pulmonary diseases, such as bacterial infections (e.g. tuberculosis and acute pneumonias) and malignancies, are addressed in Chapters 50 and 55, respectively, or are not yet amenable to drug treatment (e.g. occupational and interstitial lung diseases). Antihistamines, important in treatment of hay fever, are covered in Chapter 26. Pulmonary hypertension is covered in Chapter 22.

The Physiology of Respiration

Control of Breathing

Respiration is controlled by spontaneous rhythmic discharges from the respiratory centre in the medulla, modulated by input from pontine and higher central nervous system (CNS) centres and vagal afferents from the lungs. Various chemical factors affect the respiratory centre, including the partial pressure of carbon dioxide in arterial blood (PACO2) by an action on medullary chemoreceptors, and of oxygen (PAO2) by an action on the chemoreceptors in the carotid bodies.

Some voluntary control can be superimposed on the automatic regulation of breathing, implying connections between the cortex and the motor neurons innervating the muscles of respiration. Bulbar poliomyelitis and certain lesions in the brain stem result in loss of the automatic regulation of respiration without loss of voluntary regulation.1

Regulation of Musculature, Blood Vessels and Glands of the Airways

Irritant receptors and C fibres respond to chemical irritants and cold air, and also to inflammatory mediators (see below). Efferent pathways controlling the airways include cholinergic parasympathetic nerves and non-noradrenergic non-cholinergic (NANC) inhibitory nerves (see Ch. 12). Inflammatory mediators (see Ch. 17) and NANC bronchoconstrictor mediators also have a role in diseased airways.

The tone of bronchial muscle influences airway resistance, which is also affected by the state of the mucosa and activity of the glands in patients with asthma and bronchitis. Airway resistance can be measured indirectly by instruments that record the volume or flow of forced expiration. FEV1 is the forced expiratory volume in 1 second. The peak expiratory flow rate (PEFR) is the maximal flow (expressed as l/min) after a full inhalation; this is simpler to measure at the bedside than FEV1, which it follows closely.

Efferent Pathways

Autonomic innervation

The autonomic innervation of human airways is reviewed by van der Velden & Hulsmann (1999).

Parasympathetic innervation

Parasympathetic innervation of bronchial smooth muscle predominates. Parasympathetic ganglia are embedded in the walls of the bronchi and bronchioles, and the postganglionic fibres innervate airway smooth muscle, vascular smooth muscle and glands. Three types of muscarinic (M) receptors are present (see Ch. 13, Table 13.2). M3 receptors are pharmacologically the most important. They are found on bronchial smooth muscle and glands, and mediate bronchoconstriction and mucus secretion. M1 receptors are localised in ganglia and on postsynaptic cells, and facilitate nicotinic neurotransmission, whereas M2 receptors are inhibitory autoreceptors mediating negative feedback on acetylcholine release by postganglionic cholinergic nerves. Stimulation of the vagus causes bronchoconstriction—mainly in the larger airways. The possible clinical relevance of the heterogeneity of muscarinic receptors in the airways is discussed below.

A distinct population of NANC nerves (see Ch. 12) also regulates the airways. Bronchodilators released by these nerves include vasoactive intestinal polypeptide (Table 12.2) and nitric oxide (NO; Ch. 20).

Sympathetic innervation

Sympathetic nerves innervate tracheobronchial blood vessels and glands, but not human airway smooth muscle. β-Adrenoceptors are, however, abundantly expressed on human airway smooth muscle (as well as mast cells, epithelium, glands and alveoli) and β agonists relax bronchial smooth muscle, inhibit mediator release from mast cells and increase mucociliary clearance (see below). In humans, β-adrenoceptors in the airways are of the β2 variety.

In addition to the autonomic innervation, non-myelinated sensory fibres linked to irritant receptors in the lungs release tachykinins such as substance P, neurokinin A and neurokinin B (see Chs 19 and 41), which act on smooth muscle, secretory and inflammatory cells, producing neurogenic inflammation.

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Sensory Receptors and Afferent Pathways

Slowly adapting stretch receptors control respiration via the respiratory centre. Unmyelinated sensory C fibres and rapidly adapting irritant receptors associated with myelinated vagal fibres are also important.

Physical or chemical stimuli, acting on irritant receptors on myelinated fibres in the upper airways and/or C-fibre receptors in the lower airways, cause coughing, bronchoconstriction and mucus secretion. Such stimuli include cold air and irritants such as ammonia, sulfur dioxide, cigarette smoke and the experimental tool capsaicin (Ch. 41), as well as endogenous inflammatory mediators.

Regulation of airway muscle, blood vessels and glands image

Afferent pathways

• Irritant receptors and C fibres respond to exogenous chemicals, inflammatory mediators and physical stimuli (e.g. cold air).

Efferent pathways

• Parasympathetic nerves cause bronchoconstriction and mucus secretion through M3 receptors.
• Sympathetic nerves innervate blood vessels and glands, but not airway smooth muscle.
• β2-Adrenoceptor agonists relax airway smooth muscle. This is pharmacologically important.
• Inhibitory non-noradrenergic non-cholinergic (NANC) nerves relax airway smooth muscle by releasing nitric oxide and vasoactive intestinal peptide.
• Excitation of sensory nerves causes neuroinflammation by releasing tachykinins: substance P and neurokinin A.

Pulmonary Disease and its Treatment

Common symptoms of pulmonary disease include shortness of breath, wheeze, chest pain and cough with or without sputum production or haemoptysis—blood in the sputum. Ideally, treatment is of the underlying disease, but sometimes symptomatic treatment, for example of cough, is all that is possible. The lung is an important target organ of many diseases addressed elsewhere in this book, including infections (Chs 50–54), malignancy (Ch. 55) and occupational and rheumatological diseases; drugs (e.g. amiodarone methotrexate) can damage lung tissue and cause pulmonary fibrosis. Heart failure leads to pulmonary oedema (Ch. 22). Thromboembolic disease (Ch. 24) and pulmonary hypertension (Ch. 22) affect the pulmonary circulation. In this present chapter, we concentrate on two important diseases of the airways: asthma and COPD.

Bronchial Asthma

Asthma is the commonest chronic disease in children in economically developed countries, and is also common in adults. It is increasing in prevalence and severity. It is an inflammatory condition in which there is recurrent reversible airways obstruction in response to irritant stimuli that are too weak to affect non-asthmatic subjects. The obstruction usually causes wheeze and merits drug treatment, although the natural history of asthma includes spontaneous remissions.2 Reversibility of airways obstruction in asthma contrasts with COPD, where the obstruction is either not reversible or at best incompletely reversible by bronchodilators.

Characteristics of Asthma

Asthmatic patients experience intermittent attacks of wheezing, shortness of breath—with difficulty especially in breathing out—and sometimes cough. As explained above, acute attacks are reversible, but the underlying pathological disorder can progress in older patients to a chronic state superficially resembling COPD.

Acute severe asthma (also known as status asthmaticus) is not easily reversed and causes hypoxaemia. Hospitalisation is necessary, as the condition, which can be fatal, requires prompt and energetic treatment.

Asthma is characterised by:

• inflammation of the airways
• bronchial hyper-reactivity
• reversible airways obstruction.

The term bronchial hyper-reactivity (or hyper-responsiveness) refers to abnormal sensitivity to a wide range of stimuli, such as irritant chemicals, cold air and stimulant drugs, all of which can result in bronchoconstriction. In allergic asthma, these features may be initiated by sensitisation to allergen(s), but, once established, asthma attacks can be triggered by various stimuli such as viral infection, exercise (in which the stimulus may be cold air and/or drying of the airways) and atmospheric pollutants such as sulfur dioxide. Immunological desensitisation to allergens such as pollen or dust mites is popular in some countries but is not superior to conventional inhaled drug treatment.

Pathogenesis of Asthma

The pathogenesis of asthma involves both genetic and environmental factors, and the asthmatic attack itself consists, in many subjects, of two main phases: an immediate and a late (or delayed) phase (see Fig. 27.1).

image

Fig. 27.1 Two phases of asthma demonstrated by the changes in forced expiratory volume in 1 second (FEV1) after inhalation of grass pollen in an allergic subject.

(From Cockcroft D W 1983 Lancet ii: 253.)

Numerous cells and mediators play a part, and the full details of the complex events involved are still a matter of debate (Walter & Holtzman, 2005). The following simplified account is intended to provide a basis for understanding the rational use of drugs in the treatment of asthma.

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Asthmatics have activated T cells, with a T-helper (Th)2 profile of cytokine production (see Ch. 17 and Table 6.2) in their bronchial mucosa. How these cells are activated is not fully understood, but allergens (Fig. 27.2) are one mechanism. The Th2 cytokines that are released do the following:

• Attract other inflammatory granulocytes, especially eosinophils, to the mucosal surface. Interleukin (IL)-5 and granulocyte–macrophage colony-stimulating factor prime eosinophils to produce cysteinyl leukotrienes, and to release granule proteins that damage the epithelium. This damage is one cause of bronchial hyper-responsiveness.
• Promote immunoglobulin (Ig)E synthesis and responsiveness in some asthmatics (IL-4 and IL-13 ‘switch’ B cells to IgE synthesis and cause expression of IgE receptors on mast cells and eosinophils; they also enhance adhesion of eosinophils to endothelium).
image

Fig. 27.2 The part played by T lymphocytes in allergic asthma.

In genetically susceptible individuals, allergen (green circle) interacts with dendritic cells and CD4+ T cells, leading to the development of Th0 lymphocytes, which give rise to a clone of Th2 lymphocytes. These then (1) generate a cytokine environment that switches B cells/plasma cells to the production and release of immunoglobulin (Ig)E; (2) generate cytokines, such as interleukin (IL)-5, which promote differentiation and activation of eosinophils; and (3) cytokines (e.g. IL-4 and IL-13) that induce expression of IgE receptors. Glucocorticoids inhibit the action of the cytokines specified. APC, antigen-presenting dendritic cell; B, B cell; P, plasma cell; Th, T-helper cell.

Some asthmatics, in addition to these mechanisms, are also atopic—i.e. they make allergen-specific IgE that binds to mast cells in the airways. Inhaled allergen cross-links IgE molecules on mast cells, triggering degranulation with release of histamine and leukotriene B4, both of which are powerful bronchoconstrictors to which asthmatics are especially sensitive because of their airway hyper-responsiveness. This provides a mechanism for acute exacerbation of asthma in atopic individuals exposed to allergen. The effectiveness of omalizumab (an anti-IgE antibody; see below) serves to emphasise the importance of IgE in the pathogenesis of asthma as well as in other allergic diseases. Noxious gases (e.g. sulfur dioxide, ozone) and airway dehydration can also cause mast cell degranulation.

Clinicians often refer to atopic or ‘extrinsic’ asthma and non-atopic or ‘intrinsic’ asthma; we prefer the terms allergic and non-allergic.

Asthma image

• Asthma is defined as recurrent reversible airway obstruction, with attacks of wheeze, shortness of breath and often nocturnal cough. Severe attacks cause hypoxaemia and are life-threatening.
• Essential features include:
– airways inflammation, which causes
– bronchial hyper-responsiveness, which in turn results in
– recurrent reversible airway obstruction.
• Pathogenesis involves exposure of genetically disposed individuals to allergens; activation of Th2 lymphocytes and cytokine generation promote:
– differentiation and activation of eosinophils
– IgE production and release
– expression of IgE receptors on mast cells and eosinophils.
• Important mediators include leukotriene B4 and cysteinyl leukotrienes (C4 and D4); interleukins IL-4, IL-5, IL-13; and tissue-damaging eosinophil proteins.
• Antiasthmatic drugs include:
– bronchodilators
– anti-inflammatory agents.
• Treatment is monitored by measuring forced expiratory volume in 1 second (FEV1) or peak expiratory flow rate and, in acute severe disease, oxygen saturation and arterial blood gases.

The immediate phase of the asthmatic attack

In allergic asthma, the immediate phase (i.e. the initial response to allergen provocation) occurs abruptly and is mainly caused by spasm of the bronchial smooth muscle. Allergen interaction with mast cell-fixed IgE causes release of histamine, leukotriene B4 and prostaglandin (PG)D2 (Ch. 17).

Other mediators released include IL-4, IL-5, IL-13, macrophage inflammatory protein-1α and tumour necrosis factor (TNF)-α.

Various chemotaxins and chemokines (see Ch. 17) attract leukocytes—particularly eosinophils and mononuclear cells—into the area, setting the stage for the delayed phase (Fig. 27.3).

image

Fig. 27.3 Immediate and late phases of asthma, with the actions of the main drugs.

CysLTs, cysteinyl leukotrienes (leukotrienes C4 and D4); ECP, eosinophil cationic protein; EMBP, eosinophil major basic protein; H, histamine; iNO, induced nitric oxide.

(For more detail of the Th2-derived cytokines and chemokines, see Ch. 17 and Fig. 6.4.)

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The late phase

The late phase or delayed response (see Figs 27.1 and 27.3) may be nocturnal. It is, in essence, a progressing inflammatory reaction, initiation of which occurred during the first phase, the influx of Th2 lymphocytes being of particular importance. The inflammatory cells include activated eosinophils. These release cysteinyl leukotrienes, interleukins IL-3, IL-5 and IL-8, and the toxic proteins, eosinophil cationic protein, major basic protein and eosinophil-derived neurotoxin. These play an important part in the events of the late phase, the toxic proteins causing damage and loss of epithelium (see, for example, Larche et al., 2003; Kay, 2005). Other putative mediators of the inflammatory process in the delayed phase are adenosine (acting on the A1 receptor; see Ch. 16), induced NO (see Ch. 20) and neuropeptides (see Ch. 19).

Growth factors released from inflammatory cells act on smooth muscle cells, causing hypertrophy and hyperplasia, and the smooth muscle can itself release proinflammatory mediators and autocrine growth factors (Chs 5 and 17). Figure 27.4 shows schematically the changes that take place in the bronchioles. Epithelial cell loss means that irritant receptors and C fibres are more accessible to irritant stimuli—an important mechanism of bronchial hyper-reactivity.

image

Fig. 27.4 Schematic diagram of a cross-section of a bronchiole, showing changes that occur with severe chronic asthma.

The individual elements depicted are not, of course, drawn to scale.

‘Aspirin-sensitive’ asthma

image Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, can precipitate asthma in sensitive individuals. Such aspirin-sensitive asthma is relatively uncommon (< 10% of asthmatic subjects), and is often associated with nasal polyps. Individuals sensitive to one NSAID are usually also sensitive to other chemically unrelated cyclo-oxygenase (COX) inhibitors, including sometimes paracetamol (Ch. 26). Abnormal leukotriene production and sensitivity are implicated. Patients with aspirin-sensitive asthma produce more cysteinyl leukotriene and have greater airway hyper-responsiveness to inhaled cysteinyl leukotrienes than aspirin-tolerant asthmatics. Such airway hyper-responsiveness reflects elevated expression of cysteinyl leukotriene receptors on inflammatory cells, and this is downregulated by aspirin desensitisation (Sousa et al., 2002). In addition, aspirin and similar drugs directly activate eosinophils and mast cells in these patients through IgE-independent mechanisms.

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Drugs Used to Treat and Prevent Asthma

There are two categories of antiasthma drugs: bronchodilators and anti-inflammatory agents. Bronchodilators reverse the bronchospasm of the immediate phase; anti-inflammatory agents inhibit or prevent the inflammatory components of both phases (Fig. 27.3). These two categories are not mutually exclusive: some drugs classified as bronchodilators also have some anti-inflammatory effect.

How best to use these drugs to treat asthma is complex. A guideline (see www.brit-thoracic.org.uk, updated in 2009) specifies five therapeutic steps for adults and children with chronic asthma. Very mild disease may be controlled with short-acting bronchodilator alone (step 1), but if patients need this more than once a day, a regular inhaled corticosteroid should be added (step 2). If the asthma remains uncontrolled, the next step is to add a long-acting bronchodilator (salmeterol or formoterol); this minimises the need for increased doses of inhaled corticosteroid (step 3). Theophylline and leukotriene antagonists, such as montelukast, also exert a corticosteroid-sparing effect, but this is less reliable. One or other is added in for patients with more severe asthma who remain symptomatic and/or the dose of inhaled corticosteroid increased to the maximum recommended (step 4). If the patient’s condition is still poorly controlled, it may be necessary to add a regular oral corticosteroid (e.g. prednisolone)—step 5. Corticosteroids are the mainstay of therapy because they are the only asthma drugs that potently inhibit T-cell activation, and thus the inflammatory response, in the asthmatic airways. Cromoglicate (see below) has only a weak effect and is now seldom used.

Bronchodilators

The main drugs used as bronchodilators are β2-adrenoceptor agonists; others include theophylline, cysteinyl leukotriene receptor antagonists and muscarinic receptor antagonists.

β-Adrenoceptor agonists

The β2-adrenoceptor agonists are dealt with in Chapter 14. Their primary effect in asthma is to dilate the bronchi by a direct action on the β2 adrenoceptors of smooth muscle. Being physiological antagonists of bronchoconstrictors (see Ch. 2), they relax bronchial muscle whatever the spasmogens involved. They also inhibit mediator release from mast cells and TNF-α release from monocytes, and increase mucus clearance by an action on cilia.

The β2-adrenoceptor agonists are usually given by inhalation of aerosol, powder or nebulised solution (i.e. solution that has been converted into a cloud or mist of fine droplets), but some may be given orally or by injection. A metered-dose inhaler is used for aerosol preparations.

Two categories of β2-adrenoceptor agonists are used in asthma.

• Short-acting agents: salbutamol and terbutaline. These are given by inhalation; the maximum effect occurs within 30 min and the duration of action is 3–5 h; they are usually used on an ‘as needed’ basis to control symptoms.
• Longer-acting agents: e.g. salmeterol and formoterol. These are given by inhalation, and the duration of action is 8–12 h. They are not used ‘as needed’ but are given regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids.

Antiasthma drugs Bronchodilators image

• β2-Adrenoceptor agonists (e.g. salbutamol) are first-line drugs (for details, see Ch. 14):
– they act as physiological antagonists of the spasmogenic mediators but have little or no effect on the bronchial hyper-reactivity
– salbutamol is given by inhalation; its effects start immediately and last 3–5 h, and it can also be given by intravenous infusion in status asthmaticus
– salmeterol or formoterol are given regularly by inhalation; their duration of action is 8–12 h.

• Theophylline (often formulated as aminophylline):
– is a methylxanthine
– inhibits phosphodiesterase and blocks adenosine receptors
– has a narrow therapeutic window: unwanted effects include cardiac dysrhythmia, seizures and gastrointestinal disturbances
– is given intravenously (by slow infusion) for status asthmaticus, or orally (as a sustained-release preparation) as add-on therapy to inhaled corticosteroids and long-acting β2 agonists (step 4)
– is metabolised in the liver by P450; liver dysfunction and viral infections increase its plasma concentration and half-life (normally approximately 12 h)
– interacts importantly with other drugs; some (e.g. some antibiotics) increase the half-life of theophylline, others (e.g. anticonvulsants) decrease it.

• Cysteinyl leukotriene receptor antagonists (e.g. montelukast) are third-line drugs for asthma. They:
– compete with cysteinyl leukotrienes at CysLT1 receptors
– are used mainly as add-on therapy to inhaled corticosteroids and long-acting β2 agonists (step 4).
Unwanted effects

The unwanted effects of β2-adrenoceptor agonists result from systemic absorption and are given in Chapter 14. In the context of their use in asthma, the commonest adverse effect is tremor; other unwanted effects include tachycardia and cardiac dysrhythmia.

Clinical use of β2-adrenoceptor agonists as bronchodilators image

• Short-acting drugs (salbutamol or terbutaline, usually by inhalation) to prevent or treat wheeze in patients with reversible obstructive airways disease.
• Long-acting drugs (salmeterol, formoterol) to prevent bronchospasm (e.g. at night or with exercise) in patients requiring long-term bronchodilator therapy.

Xanthine drugs (see Chs 15 and 45)

Theophylline (1,3-dimethylxanthine), which is also used as theophylline ethylenediamine (known as aminophylline), is the main therapeutic drug of this class, and has long been used as a bronchodilator.3 Here we consider it in the context of respiratory disease, its only current therapeutic use.

Mechanism of action

The mechanism of theophylline is still unclear. The relaxant effect on smooth muscle has been attributed to inhibition of phosphodiesterase (PDE) isoenzymes, with resultant increase in cAMP and/or cGMP (see Fig. 4.10). However, the concentrations necessary to inhibit the isolated enzymes exceed the therapeutic range of plasma concentrations.

Competitive antagonism of adenosine at adenosine A1 and A2 receptors (Ch. 16) may contribute, but the PDE inhibitor enprofylline, which is a potent bronchodilator, is not an adenosine antagonist.

Type IV PDE is implicated in inflammatory cells (see below), and methylxanthines may have some anti-inflammatory effect. (Roflumilast, a type IV PDE inhibitor, is mentioned below in the context of COPD.)

Theophylline activates histone deacetylase (HDAC) and may thereby reverse resistance to the anti-inflammatory effects of corticosteroids (Barnes, 2006).

Methylxanthines stimulate the CNS (Ch. 47) and respiratory stimulation may be beneficial in patients with COPD and reduced respiration evidenced by a tendency to retain CO2 (see below).

Unwanted effects

When theophylline is used in asthma, its other actions (CNS, cardiovascular, gastrointestinal and diuretic) result in unwanted side effects (e.g. insomnia, nervousness). The therapeutic plasma concentration range is 30–100 µmol/l, and adverse effects are common with concentrations greater than 110 µmol/l; thus, there is a relatively narrow therapeutic window. Serious cardiovascular and CNS effects can occur when the plasma concentration exceeds 200 µmol/l. The most serious cardiovascular effect is dysrhythmia (especially during intravenous administration of aminophylline), which can be fatal. Seizures can occur with theophylline concentrations at or slightly above the upper limit of the therapeutic range, and can be fatal in patients with impaired respiration due to severe asthma. Monitoring the concentration of theophylline in plasma is useful for optimising the dose.

Clinical use of theophylline image

• In addition to steroids, in patients whose asthma does not respond adequately to β2-adrenoceptor agonists.
• In addition to steroids in COPD.
• Intravenously (as aminophylline, a combination of theophylline with ethylenediamine to increase its solubility in water) in acute severe asthma.
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Pharmacokinetic aspects

Theophylline is given orally as a sustained-release preparation. Aminophylline can be given by slow intravenous injection of a loading dose followed by intravenous infusion.

Theophylline is well absorbed from the gastrointestinal tract. It is metabolised by P450 enzymes in the liver; the mean elimination half-life is approximately 8 h in adults but there is wide inter-individual variation. The half-life is increased in liver disease, cardiac failure and viral infections, and is decreased in heavy cigarette smokers (as a result of enzyme induction). Unwanted drug interactions are clinically important: its plasma concentration is decreased by drugs that induce P450 enzymes (including rifampicin, phenytoin and carbamazepine). The concentration is increased by drugs that inhibit P450 enzymes, such as erythromycin, clarithromycin, ciprofloxacin, diltiazem and fluconazole. This is important in view of the narrow therapeutic window; antibiotics such as clarithromycin are often started when asthmatics are hospitalised because of a severe attack precipitated by a chest infection, and if the dose of theophylline is unaltered, severe toxicity can result.

Muscarinic receptor antagonists

Muscarinic receptor antagonists are dealt with in Chapter 13. The main compound used as a bronchodilator is ipratropium. Tiotropium is also available; it is a longer-acting drug used in maintenance treatment of COPD (see below). Ipratropium is seldom used on a regular basis in asthma but can be useful for cough caused by irritant stimuli in such patients.

Ipratropium is a quaternary derivative of N-isopropylatropine. It does not discriminate between muscarinic receptor subtypes (see Ch. 13), and it is possible that its blockade of M2 autoreceptors on the cholinergic nerves increases acetylcholine release and reduces the effectiveness of its antagonism at the M3 receptors on smooth muscle. It is not particularly effective against allergen challenge, but it inhibits the augmentation of mucus secretion that occurs in asthma and may increase the mucociliary clearance of bronchial secretions. It has no effect on the late inflammatory phase of asthma.

Ipratropium is given by aerosol inhalation. As a quaternary nitrogen compound, it is highly polar and is not well absorbed into the circulation (Ch. 8), limiting systemic effects. The maximum effect occurs approximately 30 min after inhalation and persists for 3–5 h. It has few unwanted effects and is, in general, safe and well tolerated. It can be used with β2-adrenoceptor agonists. See the clinical box, above, for clinical uses.

Clinical use of inhaled muscarinic receptor antagonists (e.g. ipratropium) image

• For asthma, as an adjunct to β2-adrenoceptor antagonists and steroids.
• For some patients with COPD, especially long-acting drugs (e.g. tiotropium).
• For bronchospasm precipitated by β2-adrenoceptor antagonists.
• For clinical uses of muscarinic receptor antagonists in other organ systems, see clinical box in Chapter 13, p. 162.

Cysteinyl leukotriene receptor antagonists

Two receptors for cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have been cloned, CysLT1 and CysLT2 (see Ch. 17), and both are expressed in respiratory mucosa and infiltrating inflammatory cells, but the functional significance of each is unclear. The ‘lukast’ drugs (montelukast and zafirlukast) antagonise only CysLT1.

Lukasts reduce acute reactions to aspirin in sensitive patients, but have not been shown to be particularly effective for aspirin-sensitive asthma (see above) in the clinic. They inhibit exercise-induced asthma and decrease both early and late responses to inhaled allergen. They relax the airways in mild asthma but are less effective than salbutamol, with which their action is additive. They reduce sputum eosinophilia, but there is no clear evidence that they modify the underlying inflammatory process in chronic asthma.

The lukasts are taken by mouth, in combination with an inhaled corticosteroid. They are generally well tolerated, adverse effects consisting mainly of headache and gastrointestinal disturbances.

Histamine H1-receptor antagonists

Although mast cell mediators play a part in the immediate phase of allergic asthma (Fig. 27.3) and in some types of exercise-induced asthma, histamine H1-receptor antagonists have no routine place in therapy, although they may be modestly effective in mild atopic asthma, especially when this is precipitated by acute histamine release in patients with concomitant allergy such as severe hay fever.

Anti-Inflammatory Agents

Glucocorticoids

Glucocorticoids (see Ch. 30) are the main drugs used for their anti-inflammatory action in asthma. They are not bronchodilators, but prevent the progression of chronic asthma and are effective in acute severe asthma (see below).4

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Actions and mechanism

The basis of the anti-inflammatory action of glucocorticoids is discussed in Chapter 32. An important action, of relevance for asthma, is that they decrease formation of cytokines, in particular the Th2 cytokines that recruit and activate eosinophils and are responsible for promoting the production of IgE and the expression of IgE receptors. Glucocorticoids also inhibit the generation of the vasodilators PGE2 and PGI2, by inhibiting induction of COX-2 (Fig. 17.1). By inducing annexin-1,5 they could inhibit production of leukotrienes and platelet-activating factor, although there is currently no direct evidence that annexin-1 is involved in the therapeutic action of glucocorticoids in human asthma.

Corticosteroids inhibit the allergen-induced influx of eosinophils into the lung. Glucocorticoids upregulate β2-adrenoceptors, decrease microvascular permeability and indirectly reduce mediator release from eosinophils by inhibiting the production of cytokines (e.g. IL-5 and granulocyte-macrophage colony stimulating factor) that activate eosinophils. Reduced synthesis of IL-3 (the cytokine that regulates mast cell production) may explain why long-term steroid treatment eventually reduces the number of mast cells in the respiratory mucosa, and hence suppresses the early-phase response to allergens and exercise.

Glucocorticoids are sometimes ineffective, even in high doses, for reasons that are incompletely understood (reviewed by Adcock & Ito, 2004). Many individual mechanisms could contribute to glucocorticoid resistance. The phenomenon has been linked to the number of glucocorticoid receptors, but in some situations other mechanisms are clearly in play—for example, reduced activity of histone deacetylase (HDAC) may be important in cigarette smokers (see below).

The main compounds used are beclometasone, budesonide, fluticasone, mometasone and ciclesonide. These are given by inhalation with a metered-dose or dry powder inhaler, the full effect on bronchial hyper-responsiveness being attained only after weeks or months of therapy.

Unwanted effects

Serious unwanted effects are uncommon with inhaled steroids. Oropharyngeal candidiasis (thrush; Ch. 52) can occur (T lymphocytes are important in protection against fungal infection), as can sore throat and croaky voice, but use of ‘spacing’ devices, which decrease oropharyngeal deposition of the drug and increase airway deposition, reduces these problems. Regular high doses can produce some adrenal suppression, particularly in children, and necessitate carrying a ‘steroid card’ (Ch. 32). This is less likely with fluticasone, mometasone and ciclesonide, as these drugs are poorly absorbed from the gastrointestinal tract and undergo almost complete presystemic metabolism. The unwanted effects of oral glucocorticoids are given in Chapter 32 and Figure 32.7.

Clinical use of glucocorticoids in asthma image

• Patients who require regular bronchodilators should be considered for glucocorticoid treatment (e.g. with inhaled beclometasone).
• More severely affected patients are treated with high-potency inhaled drugs (e.g. budesonide).
• Patients with acute exacerbations of asthma may require intravenous hydrocortisone and oral prednisolone.
• A ‘rescue course’ of oral prednisolone may be needed at any stage of severity if the clinical condition is deteriorating rapidly.
• Prolonged treatment with oral prednisolone, in addition to inhaled bronchodilators and steroids, is needed by a few severely asthmatic patients.

Cromoglicate and nedocromil

These two drugs, of similar chemical structure and properties, are now hardly used for the treatment of asthma. Although very safe, they have only weak anti-inflammatory effects and short duration of action. They are given by inhalation as aerosols or dry powders, and can be also be used topically for allergic conjunctivitis or rhinitis. They are not bronchodilators, having no direct effects on smooth muscle, nor do they inhibit the actions of any of the known smooth muscle stimulants. Given prophylactically, they reduce both the immediate- and late-phase asthmatic responses and reduce bronchial hyper-reactivity.

Their mechanism of action is not fully understood. Cromoglicate is a ‘mast cell stabiliser’, preventing histamine release from mast cells. However, this is not the basis of its action in asthma, because compounds that are more potent than cromoglicate at inhibiting mast cell histamine release are ineffective against asthma.

Cromoglicate depresses the exaggerated neuronal reflexes that are triggered by stimulation of the ‘irritant receptors’; it suppresses the response of sensory C fibres to capsaicin and may inhibit the release of T-cell cytokines. Various other effects, of uncertain importance, on the inflammatory cells and mediators involved in asthma have been described.

Anti-IgE treatment

Omalizumab is a humanised monoclonal anti-IgE antibody. It is effective in patients with allergic asthma as well as in allergic rhinitis. It is of considerable theoretical interest (see review by Holgate et al., 2005), but it is expensive and its place in therapeutics is unclear.

Antiasthma drugs Anti-inflammatory agents image

Glucocorticoids (for details, see Ch. 32)

• These reduce the inflammatory component in chronic asthma and are life-saving in status asthmaticus (acute severe asthma).
• They do not prevent the immediate response to allergen or other challenges.
• The mechanism of action involves decreased formation of cytokines, particularly those generated by Th2 lymphocytes (see key points box), decreased activation of eosinophils and other inflammatory cells.
• They are given by inhalation (e.g. beclometasone); systemic unwanted effects are uncommon at moderate doses, but oral thrush and voice problems can occur. Systemic effects can occur with high doses but are less likely with mometasone because of its presystemic metabolism. In deteriorating asthma, an oral glucocorticoid (e.g. prednisolone) or intravenous hydrocortisone is also given.

Severe Acute Asthma (Status Asthmaticus)

Severe acute asthma is a medical emergency requiring hospitalisation. Treatment includes oxygen (in high concentration, usually ≥ 60%), inhalation of nebulised salbutamol, and intravenous hydrocortisone followed by a course of oral prednisolone. Additional measures occasionally used include nebulised ipratropium, intravenous salbutamol or aminophylline, and antibiotics (if bacterial infection is present). Monitoring is by PEFR or FEV1, and by measurement of arterial blood gases and oxygen saturation.

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Allergic Emergencies

Anaphylaxis (Ch. 6) and angio-oedema are emergencies involving acute airways obstruction; adrenaline (epinephrine) is potentially life-saving. It is administered intramuscularly (or occasionally intravenously, as in anaphylaxis occurring in association with general anaesthesia). Patients at risk of acute anaphylaxis, for example from food or insect sting allergy, may self-administer intramuscular adrenaline using a spring-loaded syringe. Oxygen, an antihistamine such as chlorphenamine, and hydrocortisone are also indicated.

Angio-oedema is the intermittent occurrence of focal swelling of the skin or intra-abdominal organs caused by plasma leakage from capillaries. Most often, it is mild and ‘idiopathic’, but it can occur as part of acute allergic reactions, when it is generally accompanied by urticaria—’hives’—caused by histamine release from mast cells. If the larynx is involved, it is life-threatening; swelling in the peritoneal cavity can be very painful and mimic a surgical emergency. It can be caused by drugs, especially angiotensin-converting enzyme inhibitors—perhaps because they block the inactivation of peptides such as bradykinin (Ch. 19)—and by aspirin and related drugs in patients who are aspirin sensitive (see above and Ch. 26). The hereditary form is associated with lack of C1 esterase inhibitor—C1 esterase is an enzyme that degrades the complement component C1 (see Ch. 6). Tranexamic acid (Ch. 24) or danazol (Ch. 34) may be used to prevent attacks in patients with hereditary angioneurotic oedema, and administration of partially purified C1 esterase inhibitor or fresh plasma, with antihistamines and glucocorticoids, can terminate acute attacks. Icatibant, a peptide bradykinin B2 receptor antagonist (Ch. 16) is effective for acute attacks of hereditary angio-oedema. It is administered subcutaneously and can cause nausea, abdominal pain and nasal stuffiness.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease is a major global health problem. Cigarette smoking is the main cause, and is increasing in the developing world. Air pollution, also aetiologically important, is also increasing, and there is a huge unmet need for effective drugs. Despite this, COPD has received much less attention than asthma. A recent resurgence of interest in new therapeutic approaches (see Barnes, 2008) has yet to bear fruit.

Clinical features

The clinical picture starts with attacks of morning cough during the winter, and progresses to chronic cough with intermittent exacerbations, often initiated by an upper respiratory infection, when the sputum becomes purulent (‘bronchitis’). There is progressive breathlessness. Some patients have a reversible component of airflow obstruction identifiable by an improved FEV1 following a dose of bronchodilator. Pulmonary hypertension (Ch. 22) is a late complication, causing symptoms of heart failure (cor pulmonale). Exacerbations may be complicated by respiratory failure (i.e. reduced PAO2) requiring hospitalisation and intensive care. Tracheostomy and artificial ventilation, while prolonging survival, may serve only to return the patient to a miserable life.

Pathogenesis

There is small airways fibrosis, resulting in obstruction, and/or destruction of alveoli and of elastin fibres in the lung parenchyma. The latter features are hallmarks of emphysema,6 thought to be caused by proteases, including elastase, released during the inflammatory response. It is emphysema that causes respiratory failure, because it destroys the alveoli, impairing gas transfer. There is chronic inflammation, predominantly in small airways and lung parenchyma, characterised by increased numbers of macrophages, neutrophils and T lymphocytes. The inflammatory mediators have not been as clearly defined as in asthma. Lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines and growth factors are all implicated (Barnes, 2004).

Principles of treatment

Stopping smoking (Ch. 46) slows the progress of COPD. Patients should be immunised against influenza and Pneumococcus, because superimposed infections with these organisms are potentially lethal. Glucocorticoids are generally ineffective, in contrast to asthma, but a trial of glucocorticoid treatment is worthwhile because asthma may coexist with COPD and have been overlooked. This contrast with asthma is puzzling, because in both diseases multiple inflammatory genes are activated, which might be expected to be turned off by glucocorticoids. Inflammatory gene activation results from acetylation of nuclear histones around which DNA is wound. Acetylation opens up the chromatin structure, allowing gene transcription and synthesis of inflammatory proteins to proceed. HDAC is a key molecule in suppressing production of proinflammatory cytokines. Corticosteroids recruit HDAC to activated genes, reversing acetylation and switching off inflammatory gene transcription (Barnes et al., 2004). There is a link between the severity of COPD (but not of asthma) and reduced HDAC activity in lung tissue (Ito et al., 2005); furthermore, HDAC activity is inhibited by smoking-related oxidative stress, which may explain the lack of effectiveness of glucocorticoids in COPD.

Long-acting bronchodilators give modest benefit, but do not deal with the underlying inflammation. No currently licensed treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are in clinical development (Barnes & Stockley, 2005). Some, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma, whereas others target inflammatory cytokines such as TNF-α. PDE IV inhibitors (e.g. roflumilast; Rabe et al., 2005) show some promise. Other drugs that inhibit cell signalling (see Chs 3 and 5) include inhibitors of p38 mitogen-activated protein kinase, nuclear factor κβ and phosphoinositide-3 kinase-γ. More specific approaches are to give antioxidants, inhibitors of inducible NO synthase and leukotriene B4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is a search for serine protease and matrix metalloprotease inhibitors to prevent lung destruction and the development of emphysema.

Specific aspects of treatment

Short- and long-acting inhaled bronchodilators can provide useful palliation in patients with a reversible component. The main short-acting drugs are ipratropium and salbutamol; long-acting drugs include tiotropium and salmeterol or formoterol (Chs 13 and 14). Theophylline (Ch. 16)) can be given by mouth but is of uncertain benefit. Its respiratory stimulant effect may be useful for patients who tend to retain CO2. Other respiratory stimulants (e.g. doxapram; see Ch. 47) are sometimes used briefly in acute respiratory failure (e.g. postoperatively) but have largely been replaced by ventilatory support (intermittent positive-pressure ventilation).

Long-term oxygen therapy administered at home prolongs life in patients with severe disease and hypoxaemia (at least if they refrain from smoking—an oxygen fire is not a pleasant way to go, especially for one’s neighbours!).

Acute exacerbations

Acute exacerbations of COPD are treated with inhaled O2 in a concentration (initially, at least) of only 24% O2, i.e. only just above atmospheric O2 concentration (approximately 20%). The need for caution is because of the risk of precipitating CO2 retention as a consequence of terminating the hypoxic drive to respiration. Blood gases and tissue oxygen saturation are monitored, and inspired O2 subsequently adjusted accordingly. Broad-spectrum antibiotics (e.g. cefuroxime; Ch. 50), including activity against Haemophilus influenzae, are used if there is evidence of infection. Inhaled bronchodilators may provide some symptomatic improvement.

A systemically active glucocorticoid (intravenous hydrocortisone or oral prednisolone) is also administered routinely, although efficacy is modest. Inhaled steroids do not influence the progressive decline in lung function in patients with COPD, but do improve the quality of life, probably as a result of a modest reduction in hospital admissions.

Surfactants

Pulmonary surfactants are not true drugs in Ehrlich’s sense (Ch. 2), acting as a result of their physicochemical properties within the airways rather than by binding to specific receptors. They are effective in the prophylaxis and management of respiratory distress syndrome in newborn babies, especially if premature. Examples include beractant and poractant alpha, which are derivatives of the physiological pulmonary surfactant protein. They are administered directly into the tracheobronchial tree via an endotracheal tube. (The mothers of premature infants are sometimes treated with glucocorticoids before birth in an attempt to accelerate maturation of the fetal lung and minimise incidence of this disorder.)

Cough

Cough is a protective reflex that removes foreign material and secretions from the bronchi and bronchioles. It is a very common adverse effect of angiotensin-converting enzyme inhibitors, in which case the treatment is usually to substitute an alternative drug, notably an angiotensin receptor antagonist, less likely to cause this adverse effect (Ch. 22). It can be triggered by inflammation in the respiratory tract, for example by undiagnosed asthma or chronic reflux with aspiration, or by neoplasia. In these cases, cough suppressant (antitussive) drugs are sometimes useful, for example for the dry painful cough associated with bronchial carcinoma, but are to be avoided in cases of chronic pulmonary infection, as they can cause undesirable thickening and retention of sputum, and in asthma because of the risk of respiratory depression.

Drugs Used for Cough

Antitussive drugs in clinical use are all opioid analgesics (Ch. 41), which act by an ill-defined effect in the brain stem, depressing an even more poorly defined ‘cough centre’. They suppress cough in doses below those required for pain relief. Those used as cough suppressants have minimal analgesic actions and addictive properties. New opioid analogues that suppress cough by inhibiting release of excitatory neuropeptides through an action on µ receptors (see Table 41.1) on sensory nerves in the bronchi are being assessed.

Codeine (methylmorphine) is a weak opioid (see Ch. 41) with considerably less addiction liability than the main opioids, and is a mild cough suppressant. It decreases secretions in the bronchioles, which thickens sputum, and inhibits ciliary activity. Constipation is common. Dextromethorphan and pholcodine have similar but possibly less intense adverse effects. Respiratory depression is a risk with all drugs of this type. Morphine is used for palliative care in cases of lung cancer associated with distressing cough.

References and Further Reading

Background material

Kirstein S.L., Insel P.A. Autonomic nervous system pharmacogenomics: a progress report. Pharmacol. Rev.. 2004;56:31-52. (Reviews recent ideas regarding pharmacogenomics of components of the autonomic nervous system)

Small K.M., McGraw D.W., Liggett S.B. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu. Rev. Pharmacol. Toxicol.. 2003;43:381-411. (Reviews the consequences of adrenergic receptor polymorphisms in terms of signalling, human physiology and disease, and response to therapy)

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van der Velden V.H.J., Hulsmann A.R. Autonomic innervation of human airways: structure, function, and pathophysiology in asthma. Neuroimmunomodulation. 1999;6:145-159. (Review)

Asthma

Adcock I.M., Ito K. Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue? Curr. Opin. Pharmacol.. 2004;4:257-262. (‘Once issues of diagnosis, compliance and psychological disorder have been resolved, true steroid resistance is unlikely to be an issue for most clinicians, who will rarely, if ever, see these patients. However, management of these few patients with true steroid resistance will require novel therapies.’)

Berry M., Hargadon B., Morgan A., et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur. Respir. J.. 2005;25:986-991. (Alveolar NO as a measure of distal airway inflammation)

British Thoracic Society. (updated June, 2009). British guideline on management of asthma. http://brit-thoracic.org.uk/ClinicalInformation/Asthma/AsthmaGuidelines/tabid/83/Default.aspx, 2008.

Chatila T.A. Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol. Med.. 2004;10:493-499.

Cormican L.J., Farooque S., Altmann D.R., et al. Improvements in an oral aspirin challenge protocol for the diagnosis of aspirin hypersensitivity. Clin. Exp. Allergy. 2005;35:717-722.

Kay A.B. The role of eosinophils in the pathogenesis of asthma. Trends Mol. Med.. 2005;11:148-152. (The eosinophil is firmly back on the asthma stage, strengthening the case for developing effective eosinophil-depleting agents)

Kleeberger S.R., Peden D. Gene–environment interactions in asthma and other respiratory diseases. Annu. Rev. Med.. 2005;56:383-400.

Larche M., Robinson D.S., Kay A.B. The role of T lymphocytes in the pathogenesis of asthma. J. Allergy Clin. Immunol.. 2003;111:450-463. (Several Th2 cytokines have the potential to modulate airway inflammation, particularly IL-13, which induces airway hyper-responsiveness independently of IgE and eosinophilia in animal models)

Lucaks N.W. Role of chemokines in the pathogenesis of asthma. Nat. Rev. Immunol.. 2001;1:108-116. (Excellent coverage of the chemokines involved in asthma, with detailed table of chemokines and good diagrams)

Luster A.D., Tager A.M. T-cell trafficking in asthma: lipid mediators grease the way. Nat. Rev. Immunol.. 2004;4:711-724.

Pelaia G., Cuda G., Vatrella A., et al. Mitogen-activated protein kinases and asthma. J. Cell. Physiol.. 2005;202:642-653. (Reviews involvement of mitogen-activated protein kinases in asthma pathogenesis, and discusses their possible role as molecular targets for antiasthma drugs)

Walter M.J., Holtzman M.J. A centennial history of research on asthma pathogenesis. Am. J. Respir. Cell Mol. Biol.. 2005;32:483-489.

Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol. Rev.. 2004;202:175-190.

Chronic obstructive pulmonary disease

Barnes P.J. Mediators of chronic obstructive pulmonary disease. Pharmacol. Rev.. 2004;56:515-548. (‘The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease.’)

Barnes P.J. Frontrunners in novel pharmacotherapy of COPD. Curr. Opin. Pharmacol.. 2008;8:300-307. (Discusses candidates that may inhibit inflammation and reduce progression of COPD; most promising are theophylline-like drugs(!), new anti-oxidants and non-antibiotic macrolides)

Barnes P.J., Stockley R.A. COPD: current therapeutic interventions and future approaches. Eur. Respir. J.. 2005;25:1084-1106. (Long-acting bronchodilators have been an important advance for COPD but do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD. New approaches, for example chemokine antagonists, PDE IV inhibitors, inhibitors of p38 mitogen-activated protein kinase, nuclear factor-κβ and phosphoinositide-3 kinase-γ, are reviewed)

Barnes P.J., Ito K., Adcock I.M. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet. 2004;363:731-733. (Hypothesis that in patients with COPD, HDAC is impaired by cigarette smoking and oxidative stress, leading to reduced responsiveness to corticosteroids; see also Ito et al., 2005, below)

Ito K., Ito M., Elliott W.M., et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med.. 2005;352:1967-1976. (There is a link between the severity of COPD and the reduction in HDAC activity in the peripheral lung tissue; HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages)

Cough

Morice A.H., Kastelik J.A., Thompson R. Cough challenge in the assessment of cough reflex. Br. J. Clin. Pharmacol.. 2001;52:365-375.

Reynolds S.M., Mackenzie A.J., Spina D., Page C.P. The pharmacology of cough. Trends Pharmacol. Sci.. 2004;25:569-576. (Discusses the pathophysiological mechanisms of cough and implications for developing new antitussive drugs)

Drugs and therapeutic aspects

Barnes P.J. How corticosteroids control inflammation. Br. J. Pharmacol.. 2006;148:245-254.

Ben-Noun L. Drug-induced respiratory disorders: incidence, prevention and management. Drug Saf.. 2000;23:143-164. (Diverse pulmonary adverse drug effects)

Chrystyn H. Methods to identify drug deposition in the lungs following inhalation. Br. J. Clin. Pharmacol.. 2001;51:289-299.

Conti M., Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Ann. Rev. Biochem.. 2007;76:481-511.

Giri S.N. Novel pharmacological approaches to manage interstitial lung fibrosis in the twenty first century Annu. Rev. Pharmacol. Toxicol. 43:2003:73-95 (Reviews approaches including maintaining intracellular nicotinamide adenine dinucleotide [NAD+] and ATP, blocking transforming growth factor-β and integrins, platelet-activating factor receptor antagonists and NO synthase inhibitors)

Holgate S.T., Djukanovic R., Casale T., Bousquet J. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin. Exp. Allergy. 2005;35:408-416. (Reviews mechanism and clinical studies)

Leff A.R. Regulation of leukotrienes in the management of asthma: biology and clinical therapy. Annu. Rev. Med.. 2001;52:1-14. (Discusses the role of leukotrienes in the pathogenesis of bronchoconstriction and the pharmacology of antagonists at the cysteinyl leukotriene receptor)

Lewis J.F., Veldhuizen R. The role of exogenous surfactant in the treatment of acute lung injury. Annu. Rev. Physiol.. 2003;65:613-642.

Rabe K.F., Bateman E.D., O’Donnell D., et al. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet. 2005;366:563-571. (This type IV PDE inhibitor improved lung function and reduced exacerbations compared with placebo; the improvement was modest, and it remains to be proved that it relates to an anti-inflammatory rather than a bronchodilator action)

Sears M.R., Lotvall J. Past, present and future—β2-adrenoceptor agonists in asthma management Respir. Med. 99:2005:152-170 (‘Tolerance to the bronchoprotective effects of long-acting β2 agonists and cross-tolerance to the bronchodilator effects of short-acting β2 agonists is apparent despite use of inhaled corticosteroids. The role of β2 receptor polymorphisms in the development of tolerance has yet to be fully determined. Formoterol is unique in having both a long-lasting bronchodilator effect and a fast onset of action.’)

Sousa A.R., Parikh A., Scadding G., et al Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis N. Engl. J. Med. 347:2002:1493-1499 (Demonstrated elevated numbers of nasal inflammatory leukocytes expressing the CysLT1 receptor in biopsy specimens from aspirin-sensitive patients with chronic rhinosinusitis as compared with non-aspirin-sensitive control subjects, and downregulation of receptor expression after desensitisation to aspirin)

1Referred to as Ondine’s curse. Ondine was a water nymph who fell in love with a mortal. When he was unfaithful to her, the king of the water nymphs put a curse on him—that he must stay awake in order to breathe. When exhaustion finally supervened and he fell asleep, he died.

2William Osler, 19th-century doyen of American and British clinicians, wrote that ‘the asthmatic pants into old age’—this at a time when the most effective drug that he could offer was to smoke stramonium cigarettes, a herbal remedy the antimuscarinic effects of which were offset by direct irritation from the smoke. Its use persisted in English private schools into the 1950s as one author can attest—much to the envy of his fellows!

3Over 200 years ago, William Withering recommended ‘coffee made very strong’ as a remedy for asthma. Coffee contains caffeine, a related methylxanthine.

4In 1900, Solis-Cohen reported that dried bovine adrenals had antiasthma activity. He noted that the extract did not serve acutely ‘to cut short the paroxysm’ but was ‘useful in averting recurrence of paroxysms’. Mistaken for the first report on the effect of adrenaline, his astute observation was probably the first on the efficacy of steroids in asthma.

5Previously known as lipocortin-1—the nomenclature was changed in order to comply with the latest genomics data, which indicate there are approximately 30 members of this family!

6Emphysema is a pathological condition sometimes associated with COPD, in which lung parenchyma is destroyed and replaced by air spaces that coalesce to form bullae—blister-like air-filled spaces in the lung tissue.